Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)

ABSTRACT

The invention concerns liquid pharmaceutical formulations, for oral delivery, with modified release of active principle(s) excluding amoxicillin and consisting of suspensions of coated particles of active principles (microcapsules). The microcapsules constituting the dispersed phase of the suspension are designed, according to the invention, to enable modified release of the active principle(s), in accordance with a profile which remains unaltered during the shelf life of the liquid suspension. Therefor, the invention consists in selecting a coating composition specific to the microcapsules consisting of at least four components enabling preservation of said microcapsules in water without altering their properties of modified release of the active principle, said liquid phase being furthermore saturated with active principle(s).

The invention relates to the field of the modified release ofpharmaceutical active principles, excluding amoxicillin. In the presentdisclosure, the expression “modified release” arbitrarily denotesrelease of the active principle(s) which starts as soon as the galenicalform is brought into contact with its dissolution medium (in vivo or invitro) or release of the active principle(s) which does not start untilafter a predetermined period ranging e.g. from 0.5 to several hours. Interms of the invention, the time taken to release 50% of the activeprinciple(s) is typically several hours and can extend e.g. from 0.5 to30 hours.

More precisely, the invention relates to liquid pharmaceuticalformulations for oral administration with the modified release of activeprinciple(s), excluding amoxicillin. These formulations consist ofsuspensions or dispersions of microcapsules, each of which is formed ofa core comprising amoxicillin and of a coating enveloping said core.According to the invention, the microcapsules constituting the dispersephase of the suspension are designed to allow the modified release ofthe active principle(s), excluding amoxicillin.

Even more particularly, the invention relates especially to“multimicrocapsular” aqueous suspensions of active principle(s) for oraladministration, excluding amoxicillin, said suspensions being stablethroughout the treatment and allowing the modified release of the activeprinciple (excluding amoxicillin). These suspensions are of particularvalue in the case of:

-   -   forms for the modified release of active principles in high        therapeutic doses (for example of 500 to 1000 milligrams or        more);    -   liquid paediatric or geriatric forms for the modified release of        active principles (for example sachets or reconstitutable oral        suspensions in bottles);    -   taste masking and/or protection of sensitive active principles.

The invention further relates to a specific process for the preparationof the microcapsules to be suspended in water.

Oral pharmaceutical formulations for the modified release of activeprinciple(s) are well known.

Some of these formulations consist of tablets comprising atherapeutically active core covered with various thicknesses ofnon-digestible materials.

Microcapsules or microspheres comprising a core of active principle(s)coated with layers of different permeability or solubility have appearedmore recently. These microcapsules/microspheres are placed e.g. ingelatin capsules to form galenical systems for the modified release ofactive principle(s).

The majority of modified-release pharmaceutical forms that comprise acoated core of active ingredient(s) are presented in solid form:tablets, gelatin capsules, microspheres or microcapsules.

By way of illustration of microcapsules in the dry form, particularmention may be made of patent EP-B-0 709 087, . . . describes a(pharmaceutical or dietetic) galenical system, preferably in the form ofa tablet, advantageously a disintegrating tablet, or in the form of apowder or gelatin capsule, characterized in that it comprisesmicrocapsules of the reservoir type containing at least one medicinaland/or nutritional active principle (AP) selected especially fromantibiotics, and intended for oral administration, characterized inthat:

-   -   they consist of particles of AP each covered with a film coating        of the following composition:        -   1—at least one film-forming polymer (P1) insoluble in the            tract fluids, present in an amount of 50 to 90% by dry            weight, based on the total weight of the coating            composition, and consisting of at least one water-insoluble            cellulose derivative, ethyl cellulose and/or cellulose            acetate being particularly preferred;        -   2—at least one nitrogen-containing polymer (P2) present in            an amount of 2 to 25% by dry weight, based on the total            weight of the coating composition, and consisting of at            least one polyacrylamide and/or poly-N-vinylamide and/or            poly-N-vinyllactam, polyacrylamide and/or            polyvinylpyrrolidone being particularly preferred;        -   3—at least one plasticizer present in an amount of 2 to 20%            by dry weight, based on the total weight of the coating            composition, and consisting of at least one of the following            compounds: glycerol esters, phthalates, citrates, sebacates,            cetyl alcohol esters, castor oil, salicylic acid and cutin,            castor oil being particularly preferred;        -   4—and at least one surfactant and/or lubricant present in an            amount of 2 to 20% by dry weight, based on the total weight            of the coating composition, and selected from anionic            surfactants, preferably alkali metal or alkaline earth metal            salts of fatty acids, stearic and/or oleic acid being            preferred, and/or from non-ionic surfactants, preferably            polyethoxylated sorbitan esters and/or polyethoxylated            castor oil derivatives, and/or from lubricants such as            stearates, preferably calcium, magnesium, aluminium or zinc            stearate, or stearylfumarate, preferably sodium            stearylfumarate, and/or glycerol behenate, it being possible            for said agent to comprise only one or a mixture of the            above-mentioned products;    -   they have a particle size of between 50 and 1000 microns;    -   and they are designed so as to be able to reside in the small        intestine for a period of at least about 5 hours, thereby        allowing the absorption of the AP during at least part of their        residence time in the small intestine.

Said document relates only to dry pharmaceutical forms based onmicrocapsules and makes no mention of oral liquid pharmaceutical formsbased on microcapsules.

These modified-release solid pharmaceutical formulations are not alwaysadvantageous, especially when they are administered to very youngchildren or to very elderly patients with swallowing difficulties.

Such is the case when the active principles in question have to beadministered orally in high doses, for example of 500 to 1000 milligramsor more, e.g. when the active principle is metformin. It is clear thatsuch solid galenical systems are unsuitable because they are too bulkyand hence very difficult to swallow, especially by young children or theelderly. This can be the cause of poor patient compliance andconsequently jeopardize the success of the therapeutic treatment.

Likewise, in the case of paediatric forms, where the therapeutic dosehas to be adapted according to the child's weight, the suspensions ofthe invention are suitable for the already existing bottles providedwith syringes graduated in kg, and does not therefore necessitate thedevelopment of a novel device. The modified-release forms rarelyemployed hitherto for children are therefore now accessible by virtue ofthe invention. The advantages of such forms are the reduction in thenumber of daily dosage units and the optimization of the efficacy of thetreatment between successive dosage units (e.g. for antibiotics,anti-inflammatories, cardiovascular treatments, etc.). Thus acontrolled-release liquid pharmaceutical formulation which were easy toprepare would represent a significant advance.

In this case it would be even more advantageous to use modified-releasegalenical systems consisting of a plurality of microcapsules with adiameter of less than 1000 microns. In fact, in these systems, the doseof active principle(s) to be administered is distributed over a largenumber of microcapsules (typically 10,000 for a 500 mg dose) and thushas the following intrinsic advantages:

-   -   The use of a mixture of microcapsules with different        modified-release profiles affords release profiles which have        several release pulses or which, by appropriate regulation of        the different fractions, ensure a constant plasma concentration        level of the AP.    -   It avoids bringing the tissues into contact with a high dose of        AP (dose dumping). Each microcapsule actually contains only a        very reduced dose of active principle(s), thereby circumventing        the risk of damage to the tissues due to a local        overconcentration of aggressive active principle(s).    -   It is possible to combine several galenical forms (for immediate        or modified release) containing one or more active principles in        these “multimicrocapsular” systems.

Liquid multiparticulate galenical forms or, more precisely, colloidalsuspensions are known which are preferred to the solid forms for oraladministration in the case of high-dosage active principles orpaediatric applications.

Liquid suspensions for the modified release of active principle(s) aredifficult to produce. The main difficulty to be overcome is that ofavoiding the release of the active principle(s) into the liquid phaseduring storage of the suspension, while allowing modified release assoon as it enters the gastrointestinal tract. This objective isparticularly difficult to achieve because the active principle(s) is(are) stored in a liquid for a very long time compared with the desiredrelease time in the gastrointestinal tract fluids. Furthermore, itsprolonged residence in the liquid phase during storage must not perturbthe modified-release system to the point of degrading the releaseprofile and release time of the active principle(s).

Furthermore, for these liquid formulations to be fully effective, it isknown to be important that:

-   -   the microcapsules are very small (<1000 microns),    -   and the weight fraction of coating excipients is limited, this        modality being all the more difficult to achieve because, due to        their small size, the microcapsules have a large specific        surface area, accelerating the release.

As regards the prior art concerning oral liquid pharmaceutical forms forthe modified release of active principles, French patent applicationFR-A-2 634 377 should be mentioned first of all; said document disclosesa novel modified-release pharmaceutical form based on a resin/activeprinciple complex coated with an ionic polymer whose polarity isopposite to that of the resin, and fixed thereto by ionic bonding. Theactive principle is also ionic and has a polarity opposite to that ofthe resin. The latter can be sodium polystyrenesulfonate and the ioniccoating polymer is selected from acrylic and methacrylic acid esterpolymers (EUDRAGIT®). The resin is impregnated with an aqueous solutionof the active principle. The resin particles impregnated with activeprinciple are then coated with an organic solution of ionic polymer. Theresulting microcapsules can be converted to an oral suspension (Example2 in particular). The use of an ionic resin and an ionic coating polymerlimits the possible applications to ionic active principles.

American patents U.S. Pat. No. 4,999,189 and U.S. Pat. No. 5,186,930relate to liquid pharmaceutical compositions comprising ion exchangeionic resin/active principle complexes suspended in a liquid phase.These particles of resin/active principle complex are coated with afirst layer of pharmaceutically acceptable wax of high melting point andwith a second, outer layer of a pharmaceutically acceptablewater-insoluble polymer (ethyl cellulose, methyl cellulose,hydroxypropyl methyl cellulose, hydroxyethyl cellulose, Eudragit®,etc.). A plasticizer such as dibutyl sebacate can be introduced intothis second, outer layer. The active principle is fixed by ionic bondingto the ion exchange resin. The liquid phase consists of a glucose syrupwith a high fructose content and of several other ingredients such asglycerol or propylene glycol.

U.S. Pat. No. 5,186,930 differs from the first U.S. patent in that itmakes provision for a sufficient amount of the first layer (wax) toprevent the particles of resin/active principle complexes from swellingand crackling.

These U.S. patents do not provide any data that allow the quality of themodified release of active principles to be assessed. Moreover, usingion exchange resins as the active principle support is ratherinconvenient and restrictive in terms of the variety of activeprinciples involved. Furthermore, this galenical system has nothingconvincing to offer in terms of the stability and preservation of themodified-release properties of the active principle.

PCT patent application WO-A-87/07833 and patent U.S. Pat. No. 4,902,513disclose aqueous suspensions of microcapsules of active principle (e.g.theophylline) with modified release of the active principle (e.g. 12 h).These suspensions are prepared by saturating the aqueous phase with theactive principle before incorporating the microcapsules of activeprinciple into this aqueous phase. The composition of the coating agentfor the microcapsules that allows the modified release of the activeprinciple is not described in said documents. Now, this coatingcomposition is a decisive factor in guaranteeing the maintenance of themodified-release profile of the microcapsules after storage in theaqueous phase. The technical proposal described appears not to disclosethe means of solving the dual problem of producing a liquid suspensionof a modified-release microcapsular form without interfering with thestability of the modified-release profile of the active principle afterthe microcapsules have been stored in the liquid phase.

European patent application EP-A-0 601 508 relates to an aqueoussuspension for the oral administration of naxopren according to amodified-release profile. This suspension comprises coated microgranulesof naxopren suspended in a syrupy aqueous liquid phase. The technicalproblem underlying this invention is to provide a modified-release formof naxopren containing a 1000 mg dose and capable of administration in asingle daily dosage unit.

The microgranules consist of naxopren, polyvinylpyrrolidone and lactose(90-300 μm). Their coating is made up of 4 layers. The first comprisesdiethyl cellulose/diethyl phthalate/polyethylene glycol. The second isbased on EUDRAGIT (meth)acrylate/(meth)acrylic copolymers. The thirdcomprises glycerol stearate/wax/fatty alcohols and the fourth consistsof an enteric covering based on cellulose acetate/phthalate. Thenaxopren undergoes modified release over 24 hours.

Example 22 of said European patent application EP-A-0 601 508 contains ademonstration of the stability of the release profile after 30 days'storage of the liquid suspension.

One of the disadvantages of this suspension derives from the entericlayer, which prohibits the use of a suspension of neutral pH becausethis layer is designed to disintegrate and become liquid at neutral pH.Another disadvantage of this enteric layer is that it blocks the releaseof the active principle in the stomach at acidic pH. Now, for AP whoseabsorption window is situated in the upper parts of the gastrointestinaltract, it is often advantageous to release the active principle in thestomach in order to increase the bioavailability. Furthermore, thismultilayer solution to the problem is very complex and in additionspecific to naproxen.

PCT patent application WO-A-96/01628 discloses a liquid pharmaceuticalformulation for the oral administration, according to a modified-releaseprofile (12 hours), of an active principle consisting of moguisteine.The object is to propose a modified-release liquid formulation ofmoguisteine which is easy to measure out and ingest, has a release timethat makes it possible to avoid multiple dosage units, is stable overtime in aqueous suspension and is pleasantly flavoured in order tofavour compliance, and whose manufacture does not involve the use oftoxic substances like solvents. To achieve this object, the inventionaccording to PCT patent application WO-A-96/01628 proposes a suspension,in a weakly hydrated liquid phase (essentially based on sorbitol andglycerol), of microgranules (90-300 μm) of moguisteine coated with afirst, hydrophilic layer consisting of cellulose acetate/phthalate anddiethyl phthalate, a second, hydrophobic layer containing glycerolstearate/wax/fatty alcohols, and a third, hydrophilic layer identical tothe first.

This multilayer form is very complex to prepare and in addition isspecific to moguisteine.

In this state of the art, the essential objective of the presentinvention is to propose an aqueous suspension of microcapsules of activeprinciple(s), excluding amoxicillin, for the oral administration of thelatter according to a modified-release profile, in which the coating ofthe microcapsules is designed in such a way that the release profile isnot perturbed and does not depend on the maceration time of themicrocapsules in the liquid (preferably aqueous) phase. Thus the activeprinciple(s) contained in the microcapsules would be prevented fromescaping into the liquid phase throughout the storage of the suspension,but a modified release of the active principle(s) would be allowed assoon as it entered an environment suitable for triggering the release,namely in vivo in the gastrointestinal tract and in vitro under theconditions of a dissolution test performed just after suspension of themicrocapsules in the solvent (preferably aqueous) phase, using a type IIapparatus according to the European Pharmacopoeia 3rd edition, in aphosphate buffer medium of pH 6.8, for a volume of 900 ml, at atemperature of 37° C.

Another objective of the present invention is to provide an aqueousliquid suspension of microcapsules of active principle(s) (excludingamoxicillin) comprising a film coating formed of a single layer.

Another objective of the present invention is to provide an aqueousliquid suspension of microcapsules of active principle(s) (excludingamoxicillin) in which the dissolved fraction originating from themicrocapsules is less than or equal to 15% and preferably 5% of thetotal weight of active principles present in the microcapsules.

Another objective of the present invention is to provide an aqueousliquid suspension of microcapsules of active principle(s) (excludingamoxicillin) in which one part of the active principle(s) is in animmediate-release form and the other part of the active principle(s) isin a modified-release form (microcapsules).

Another essential objective of the present invention is to provide anaqueous suspension of microcapsules for the modified release of activeprinciples (excluding amoxicillin) which makes it possible to releasethe active principle according to a release profile that is not degradedby the ageing of the suspension.

Another essential objective of the present invention is to provide anaqueous suspension of microcapsules which is made up of individuallycoated particles of active principle(s) (excluding amoxicillin) andmakes it possible to release the latter according to a prolonged and/oroptionally delayed profile such that the release half-life t,/, isbetween 0.5 and 30 hours.

Another objective of the present invention is to propose an oralgalenical form which is liquid and consists of a large number (forexample in the order of several thousands) of microcapsules, thismultiplicity statistically ensuring a good reproducibility of thetransit kinetics of the AP throughout the gastrointestinal tract,thereby improving control of the bioavailability and hence improvingefficacy.

One essential objective of the present invention is to propose an oralliquid galenical form made up of a plurality of coated microcapsuleswhich avoids the use of large amounts of coating agent, the weightfraction of coating agent being comparable to that of the monolithicforms.

Another essential objective of the present invention is to provide amodified-release aqueous suspension in which the active principle(s)(excluding amoxicillin) is (are) in the form of a plurality of particlesindividually coated to form microcapsules and allowing the mixing ofseveral active principles having different respective release times.

Another essential objective of the present invention is to propose theuse, as a means of treating human or veterinary diseases, of a(preferably aqueous) suspension of microcapsules consisting of particlesof active principle(s) (excluding amoxicillin) individually coated so asto determine the modified release of the active principle(s) without themodified-release profile being affected by storage of the microcapsulesin this liquid form in suspension.

Another essential objective of the present invention is to propose adrug based on a preferably aqueous suspension of microcapsulesconsisting of particles of active principle(s) (excluding amoxicillin)individually coated so as to determine the modified release of theactive principle(s) without the modified-release profile being affectedby storage of the microcapsules in this liquid form in suspension.

Having set themselves all the above objectives, among others, theinventors have succeeded in developing a multimicrocapsular galenicalsystem in the form of a preferably aqueous suspension for the modifiedrelease of active principle(s), excluding amoxicillin, which:

-   -   does not degrade the optionally retarded, modified-release        profile,    -   and is stable, easy to prepare, economic and effective.

To do this the inventors have proposed to:

-   -   select a totally specific coating composition for the        microcapsules,    -   and suspend the microcapsules in a (preferably aqueous) liquid        phase saturated with active principle(s) or capable of being        saturated with active principle(s) on contact with the        microcapsules, using an amount of solvent (preferably water)        that is limited but nevertheless sufficient for the suspension        to be easy to swallow.

Thus the invention which meets the objectives described above, amongothers, relates to a suspension of microcapsules in an aqueous liquidphase that allows the modified release of at least one active principle(excluding amoxicillin) and is intended for oral administration,characterized in that:

-   -   it comprises a plurality of microcapsules each consisting of a        core containing at least one active principle (excluding        amoxicillin) and of a film coating that:        -   is applied to the core,        -   controls the modified release of the active principle(s),        -   and has a composition corresponding to one of the following            three families A, B and C:            -   Family A            -   1A—at least one film-forming polymer (P1) insoluble in                the tract fluids, present in an amount of 50 to 90 and                preferably of 50 to 80% by dry weight, based on the                total weight of the coating composition, and consisting                of at least one water-insoluble cellulose derivative;            -   2A—at least one nitrogen-containing polymer (P2) present                in an amount of 2 to 25 and preferably of 5 to 15% by                dry weight, based on the total weight of the coating                composition, and consisting of at least one                polyacrylamide and/or poly-N-vinylamide and/or                poly-N-vinyllactam;            -   3A—at least one plasticizer present in an amount of 2 to                20 and preferably of 4 to 15% by dry weight, based on                the total weight of the coating composition, and                consisting of at least one of the following compounds:                glycerol esters, phthalates, citrates, sebacates, cetyl                alcohol esters and castor oil;            -   4A—at least one surfactant and/or lubricant present in                an amount of 2 to 20 and preferably of 4 to 15% by dry                weight, based on the total weight of the coating                composition, and selected from anionic surfactants                and/or non-ionic surfactants and/or lubricants, it being                possible for said agent to comprise only one or a                mixture of the above-mentioned products;            -   Family B            -   1B—at least one hydrophilic polymer carrying groups                ionized at neutral pH and preferably selected from                cellulose derivatives;            -   2B—at least one hydrophobic compound different from A;            -   Family C            -   1C—at least one film-forming polymer insoluble in the                gastrointestinal tract fluids;            -   2C—at least one water-soluble polymer;            -   3C—at least one plasticizer;            -   4C—optionally at least one surfactant/lubricant                preferably selected from the following group of                products:            -   anionic surfactants;            -   and/or non-ionic surfactants,    -   and the liquid phase is saturated or becomes saturated with        active principle(s) on contact with the microcapsules.

In terms of the present disclosure, the expression “microcapsules ofactive principle(s)” denotes microcapsules whose core comprises one ormore active principles and optionally at least one excipient.

This suspension according to the invention makes it possible to overcomethe two main obstacles to the production of an aqueous suspension ofmicrocapsules consisting of individually coated microparticles of activeprinciples and allowing the modified release of the latter, these twoobstacles being as follows:

-   -   a) limiting the fraction of active principles immediately        releasable from the microcapsules to a value of less than 15%        and preferably 5% of the total weight of active principles used        in the microcapsules;    -   b) obtaining a modified-release system that is sufficiently        robust to avoid any change or degradation of the release profile        of the active principle(s) during storage of the aqueous        suspension.

Also, this suspension makes it possible to facilitate the oraladministration of drugs which have high therapeutic doses, especially inthe case of the elderly and children, there being a significant gain interms of compliance and success of the treatment.

Furthermore, for AP which have a limited absorption window, it isparticularly advantageous for the modified-release form to be aplurality of microcapsules, as indicated in the preamble of the presentdisclosure.

In one preferred embodiment of the invention, the families A, B and Cfrom which the constituents of the coating composition are selected areas follows:

Family A

-   -   1A—ethyl cellulose and/or cellulose acetate;    -   2A—polyacrylamide and/or polyvinylpyrrolidone;    -   3A—castor oil;    -   4A—an alkali metal or alkaline earth metal salt of fatty acids,        stearic and/or oleic acid being preferred, a polyethoxylated        sorbitan ester, a polyethoxylated castor oil derivative, a        stearate, preferably calcium, magnesium, aluminium or zinc        stearate, a stearylfumarate, preferably sodium stearylfumarate,        or glycerol behenate, taken individually or in a mixture with        one another;

Family B

-   -   cellulose acetate-phthalate;    -   hydroxypropyl methyl cellulose phthalate;    -   hydroxypropyl methyl cellulose acetate-succinate;    -   (meth)acrylic acid/(meth)acrylic acid alkyl (methyl) ester        copolymer (EUDRAGIT® S or L);    -   and mixtures thereof;    -   2B    -   hydrogenated vegetable waxes (Dynasan® P60, Dynasan® 116);    -   triglycerides (tristearin, tripalmitin, Lubritab®, Cutina HR,        etc.);    -   animal and vegetable fats (beeswax, camauba wax, etc.);    -   and mixtures thereof.

Family C

-   -   1C    -   water-insoluble cellulose derivatives, ethyl cellulose and/or        cellulose acetate being particularly preferred;    -   acrylic derivatives;    -   polyvinyl acetates;    -   and mixtures thereof;    -   2C    -   water-soluble cellulose derivatives;    -   polyacrylamides;    -   poly-N-vinylamides;    -   poly-N-vinyllactams;    -   polyvinyl alcohols (PVA);    -   polyoxyethylenes (POE);    -   polyvinylpyrrolidones (PVP) (the latter being preferred);    -   and mixtures thereof;    -   3C    -   glycerol and its esters, preferably from the following subgroup:        acetylated glycerides, glycerol monostearate, glyceryl        triacetate and glycerol tributyrate;    -   phthalates, preferably from the following subgroup: dibutyl        phthalate, diethyl phthalate, dimethyl phthalate and dioctyl        phthalate;    -   citrates, preferably from the following subgroup: acetyltributyl        citrate, acetyltriethyl citrate, tributyl citrate and triethyl        citrate;    -   sebacates, preferably from the following subgroup: diethyl        sebacate and dibutyl sebacate;    -   adipates;    -   azelates;    -   benzoates;    -   vegetable oils;    -   fumarates, preferably diethyl fumarate;    -   malates, preferably diethyl malate;    -   oxalates, preferably diethyl oxalate;    -   succinates, preferably dibutyl succinate;    -   butyrates;    -   cetyl alcohol esters;    -   salicylic acid;    -   triacetin;    -   malonates, preferably diethyl malonate;    -   cutin;    -   castor oil (this being particularly preferred);    -   and mixtures thereof;    -   4C    -   alkali metal or alkaline earth metal salts of fatty acids,        stearic and/or oleic acid being preferred;    -   polyethoxylated oils, preferably polyethoxylated hydrogenated        castor oil;    -   polyoxyethylene/polyoxypropylene copolymers;    -   polyethoxylated sorbitan esters;    -   polyethoxylated castor oil derivatives;    -   stearates, preferably calcium, magnesium, aluminium or zinc        stearate;    -   stearylfumarates, preferably sodium stearylfumarate;    -   glycerol behenate;    -   and mixtures thereof.

Preferably, the film coating consists of a single layer whose weightrepresents from 1 to 50% and preferably from 5 to 40% of the totalweight of the microcapsules.

According to one preferred characteristic of the invention, the liquidphase is aqueous; even more preferably, it contains at least 20% ofwater and preferably at least 50% by weight of water.

This suspension according to the invention advantageously contains:

-   -   30 to 95% by weight and preferably 60 to 85% by weight of liquid        phase (advantageously water);    -   and 5 to 70% by weight and preferably 15 to 40% by weight of        microcapsules.

Advantageously, the amount of solvent liquid phase (preferably water)for the active principle(s) (excluding amoxicillin) is such that theproportion of dissolved active principle(s) originating from themicrocapsules is less than or equal to 15% and preferably less than orequal to 5% by weight, based on the total weight of the activeprinciple(s) contained in the microcapsules.

In a first embodiment of the invention, the liquid phase is at leastpartially and preferably totally saturated with active principle(s)(excluding amoxicillin) following the incorporation of the microcapsulesinto this liquid phase.

In this embodiment, it is the active principle(s) contained in themicrocapsules that saturate the liquid phase.

In a second embodiment of the invention, the liquid phase is at leastpartially and preferably totally saturated with active principle(s)(excluding amoxicillin) by means of non-encapsulated active principle(s)prior to the incorporation of the microcapsules into this liquid phase.This embodiment is of particular value for the administration ofamoxicillin in that it makes it possible to combine an immediate-releasefraction with a modified-release fraction.

In practice, this amounts to saturating the liquid phase with activeprinciple(s) before the introduction of the microcapsules into thesuspension, so that the active principle contained in the microcapsulesplays no part, or virtually no part, in the saturation of the liquidphase. The diffusion of the active principle contained in themicrocapsules is therefore suppressed or virtually suppressed.

According to one preferred characteristic of the invention enabling thisliquid oral formulation to be fully effective, the microcapsules have aparticle size less than or equal to 1000 microns, preferably of between200 and 800 microns and particularly preferably of between 200 and 600microns.

“Particle size” is understood in terms of the invention as meaning thata proportion of at least 75% by weight of microcapsules have a diameterbetween the screen size limits in question.

Again with the aim of improving efficacy, the amount of coating agentfor the microcapsules advantageously represents from 1 to 50% andpreferably 5 to 40% of the weight of the coated microcapsules. Thisadvantageous characteristic is all the . . . to acquire because, due totheir small size, the microcapsules have a large specific surface area,accelerating the release.

To control the in vivo in vitro release of the active principle(s), itis preferable according to the invention to use a film coating for themicrocapsules which belongs to family A or C.

For more detailed qualitative and quantitative information on thiscoating composition of family A, reference may be made to Europeanpatent EP-B-0 709 087, the content of which forms part of the presentdisclosure by way of reference.

Another possible way of defining the liquid suspension according to theinvention consists in considering an in vitro release profile obtainedusing a type II apparatus according to the European Pharmacopoeia 3rdedition, in a phosphate buffer medium of pH 6.8 and at a temperature of37° C., such that:

-   -   the proportion PI of active principle(s) released from the        microcapsules during the first 15 minutes of the dissolution        test is such that:        PI≦15        preferably PI≦5;    -   the active principle(s) remaining in the microcapsules is (are)        released over a period such that the release time of 50% by        weight of AP (t_(1/2)) is defined as follows (in hours):        0.5≦t_(1/2)≦30        preferably 0.5≦t_(1/2)≦20.

Still with regard to its in vitro dissolution properties, the suspensionaccording to the invention is characterized in that:

-   -   the initial in vitro release profile Pfi obtained just after        suspension of the microcapsules in the solvent (preferably        aqueous) phase, using a type II apparatus according to the        European Pharmacopoeia 3rd edition, in a phosphate buffer medium        of pH 6.8, for a volume of 900 ml, at a temperature of 37° C.,    -   and the in vitro release profile Pf₁₀ obtained 10 days after        suspension of the microcapsules in the solvent (preferably        aqueous) phase, using a type II apparatus according to the        European Pharmacopoeia 3rd edition, in a phosphate buffer medium        of pH 6.8, at a temperature of 37° C., are similar.

The release profiles compared according to the recommendations of TheEuropean Agency for the Evaluation of Medicinal Products (EMEA)—HumanMedicines Evaluation Unit—/Committee for proprietary medicinal products(CPMP)—London, 29 Jul. 1999, CPMP/QWP/604/96: note for guidance onquality of modified release products: A: oral dosage forms, B:transdermal dosage forms—section I (quality)—Annex 3: Similarity factorf ₂, produce a value of >50 for the similarity factors f₂ and cantherefore be declared similar.

These advantageous characteristics of the suspension according to theinvention enable high doses of active principle(s) to be administeredorally without difficulty and without detracting from the modified andoptionally delayed release mode of the active principle.

According to another of its advantageous physicochemicalcharacteristics, the pH of the liquid suspension according to theinvention can arbitrarily be acidic or neutral.

It may be quite valuable to add at least one rheology modifier to thesuspension. In particular, this can be one or more “viscosifiers”selected . . . those commonly employed in the pharmaceutical industryand especially those disclosed in Handbook of pharmaceuticalexcipients—3rd edition, Am. Pharmaceutical Association, Arthur H. KIBBE,2000, ISBN 091 7330-96-X. Europe. 0-85369-381-1. Examples which may bementioned are:

-   -   water-soluble cellulose derivatives (hydroxyethyl cellulose,        hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl        methyl cellulose, etc.);    -   polyethylene glycols;    -   alginates and derivatives thereof;    -   carrageenans;    -   agar-agar;    -   gelatin;    -   maltodextrins;    -   polydextrose;    -   guar, carob, acacia, xanthan, gellan and other gums;    -   polyvinyl alcohol;    -   povidone;    -   pectins;    -   silica gel;    -   native and modified starches and derivatives thereof;    -   dextrans;    -   etc.

It can also be advisable to introduce into the suspension at least oneagent for modifying the solubility of the active principle in thesolvent (preferably aqueous) liquid phase, for example salts, sugars,glycerol, etc. In fact, in the case of very soluble active principles,these solutes can limit the escape of the active principle from themicrocapsules by lowering the saturation concentration of the activeprinciple in the aqueous phase.

For the suspension to have all the qualities of an oral galenical formthat is easy to swallow, stable and palatable, it advantageouslycontains at least one other additive selected from the group comprisingsurfactants, colourants, dispersants, preservatives, taste improvers,flavourings, sweeteners, antioxidants and mixtures thereof.

Examples of these additives which may be mentioned are those commonlyemployed in the pharmaceutical industry and especially those disclosedin Handbook of pharmaceutical excipients—3rd edition, Am. PharmaceuticalAssociation, Arthur H. KIBBE, 2000, ISBN 0917330-96-X Europe.0-85369-381-1, or, in the case of emulsifiers, those described on page5, lines 14 to 29, of EP-A-0 273 890, or again, in the case ofthickeners, those indicated on page 5, lines 19 and 20, of EP-A-0 601508.

The active principles used to prepare the controlled-release suspensionsaccording to the invention can be selected from at least one of thefollowing wide varieties of active substances: antiulcer drugs,antidiabetics, anticoagulants, antithrombics, hypolipidaemics,antiarrhythmics, vasodilators, antiangina drugs, antihypertensives,vasoprotectors, fertility promoters, labour inducers and inhibitors,contraceptives, antibiotics, antifungals, antivirals, anticancer drugs,anti-inflammatories, analgesics, antiepileptics, antiparkinsonism drugs,neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigrainedrugs, antidepressants, antitussives, antihistamines and antiallergics.

Without implying a limitation, the invention applies more particularlyto pharmaceutical active principles which have to be administered orallyin high doses, for example of 500 to 1000 milligrams or more, and topaediatric suspensions.

The active principle(s) is (are) preferably selected from the followingcompounds: pentoxifylline, prazosin, aciclovir, nifedipine, diltiazem,naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin,diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride,captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol,salbutamol, carbamazepine, ranitidine, enalapril, simvastatin,fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir,spironolactone, 5-asa, quinidine, perindopril, morphine, pentazocine,metformin, paracetamol, omeprazole, metoclopramide, atenolol, salbutamolmorphine, verapamil, erythromycin, caffeine, furosemide, cephalosporins,montelukast, valaciclovir, ascorbic acid salts, diazepam, theophylline,ciprofloxacin, vancomycin, aminoglycosides, penicillins (except foramoxicillin) and mixtures thereof.

According to another of its features, the present invention relates to adrug, characterized in that it comprises a suspension ofmodified-release microcapsules of active principle(s), as defined above.

In more concrete terms, the invention further relates to a drug, or moreexactly a galenical pack, characterized in that it comprises a kit forpreparing the suspension as defined above, said kit containing:

-   -   microcapsules in substantially dry form containing the active        principle(s) for saturating the liquid phase with active        principle(s) once the two solid and liquid phases have been        brought into contact;    -   and/or a mixture of microcapsules in substantially dry form        containing the active principle(s) in the dose that is just        necessary for modified release, together with immediate-release        uncoated active principle(s) in a necessary and sufficient        amount to saturate the liquid phase with active principle(s)        once the saturation dose of active principle(s) and the liquid        phase have been brought into contact;    -   and the liquid phase and/or at least part of the ingredients        useful for its preparation, and/or the protocol for preparation        of the suspension.

This type of presentation of the drug according to the invention enablespatients easily to prepare the modified-release suspension in a formthat is stable, particularly in terms of modified release, for at leastseveral days. The patient is thus guaranteed to have a drug that is easyto administer orally and perfectly effective from the therapeutic pointof view.

The microcapsules constituting the solid phase of the suspensionaccording to the invention can be prepared by microencapsulationtechniques available to those skilled in the art, the main techniquesbeing summarized in the article by C. DUVERNEY and J. P. BENOIT in“L'actualité chimique”, December 1986. More precisely, the technique inquestion is microencapsulation by film coating, which yieldsindividualized “reservoir” systems as opposed to matrix systems.

For further details, reference may be made to patent EP-B-0 953 359cited above.

To produce the core based on active principle(s) (excluding amoxicillin)of the microcapsules according to the invention, it is advantageous touse, as starting materials, particles of active principle(s) of thedesired size. Said particles can be crystals of active principle(s)which are pure and/or have undergone a pretreatment by one of thetechniques conventionally employed in the art, for example granulation,in the presence of a small amount of at least one conventional binderand/or an agent for modifying the intrinsic solubility characteristicsof the AP.

The invention will be understood more clearly from the point of view ofits composition, properties and preparation with the aid of the Examplesbelow, given solely by way of illustration, which demonstrate thevariants and the advantages of the invention.

DESCRIPTION OF FIGURES

FIG. 1 shows the initial dissolution profile and the dissolution profileafter 10 days' storage of the suspension according to Example 1, in %dissolved (D) as a function of the time (t) in hours.

FIG. 2 shows the initial dissolution profile and the dissolution profileafter 19 days' storage of the suspension according to Example 2, in %dissolved (D) as a function of the time (t) in hours.

FIG. 3 shows the initial dissolution profile and the dissolution profileafter 12 days' storage of the suspension according to Example 3, in %dissolved (D) as a function of the time (t) in hours. This suspensioncombines 29% of free metformin with 71% of encapsulated metformin.

EXAMPLE 1

Preparation of Microcapsules of Aciclovir:

1000 g of aciclovir and 30 g of povidone® are mixed dry for 5 minutes.The mixture is granulated with water. The granules are dried at 40° C.in a ventilated oven and then graded on a 500 μm screen. The 200-500 μmfraction is selected.

700 g of granules obtained above are coated with 27.3 g of ethylcellulose, 3.7 g of castor oil, 3.7 g of magnesium stearate and 2.9 g ofpovidone® dissolved in a 60/40 w/w acetone/isopropanol mixture, in aGlatt GPC-G1 fluidized air bed apparatus. Temperature of product: 40° C.

Preparation of the Suspension:

0.58 g of microcapsules obtained above is placed in 37 ml of phosphatebuffer of pH 6.8.

Test:

The above suspension is stored for 10 days at room temperature. After 10days the suspension is analysed for dissolution using a type IIapparatus according to the European Pharmacopoeia 3rd edition, phosphatebuffer medium of pH 6.8, volume of 900 ml, temperature of 37° C., bladestirring at 100 rpm, UV detection at 252 nm.

The result is shown in FIG. 1 attached.

The profiles are apparently identical: similarity factor f₂ greater than50. The microcapsules remain highly effective in aqueous suspension.

EXAMPLE 2

Preparation of Microcapsules of Spironolactone:

Step 1: Granules

45 g of spironolactone, 25 g of PEG 40—hydrogenated castor oil and 30 gof povidone are first solubilized in a water/acetone/isopropanol mixture(5/57/38 w/w). This solution is then sprayed onto 800 g of cellulosespheres (of diameter between 300 and 500 □m) in a Glatt GPC-G1 fluidizedair bed apparatus.

Step 2: Coating

50 g of granules obtained above are coated with 1.44 g of ethylcellulose, 0.16 g of castor oil, 0.64 g of poloxamer 188 and 0.96 g ofpovidone dissolved in an acetone/isopropanol mixture (60/40 w/w), in aminiGlatt fluidized air bed apparatus.

Preparation of the Suspension:

0.07 g of microcapsules obtained above is placed in 0.165 ml ofphosphate buffer of pH 6.8.

Test:

The above suspension is stored for 19 days at room temperature. After 19days the suspension is analysed for dissolution using a type IIapparatus according to the European Pharmacopoeia 3rd edition, phosphatebuffer medium of pH 6.8, volume of 1000 ml, temperature of 37° C., bladestirring at 100 rpm, UV detection at 240 nm.

The result is shown in FIG. 2 attached.

The profiles are apparently identical: similarity factor f₂ greater than50. The microcapsules remain very effective in aqueous suspension.

EXAMPLE 3

Preparation of Microcapsules of Metformin:

740 g of metformin crystals (200-500 μm fraction) are coated with 192.4g of ethyl cellulose, 26 g of castor oil, 26 g of magnesium stearate and20.8 g of povidone® dissolved in a 60/40 w/w acetone/isopropanolmixture, in a Glatt GPC-G1 fluidized air bed apparatus. Temperature ofproduct: 40° C.

Preparation of the Suspension (29% of Free Form and 71% of EncapsulatedForm):

50 g of microcapsules obtained above are mixed dry with 15 g ofmetformin crystals and 0.7 g of xanthan gum in a 100 ml glass flask.34.3 g of purified water are then added to the powder mixture. Aftermanual stirring, a suspension is obtained which produces a sediment veryslowly.

The total metformin titre in the suspension is 0.52 g/ml.

Stability Test:

The above suspension is stored for 12 days at room temperature. After 12days the suspension is analysed for dissolution using a type IIapparatus according to the European Pharmacopoeia 3rd edition, phosphatebuffer medium of pH 6.8, volume of 900 ml, temperature of 37° C., bladestirring at 100 rpm, UV detection at 232 nm.

The result is shown in FIG. 3 attached.

The profiles are apparently identical: similarity factor f₂ greater than50. The microcapsules remain very effective in aqueous suspension.

Homogeneity Test:

The above suspension is stirred manually and then six 5 ml samples aretaken with a graduated syringe. The metformin content of each sample isdetermined by HPLC and is shown below:

Metformin content for 5 ml Sample no. of suspension (in g) 1 2.58 2 2.603 2.62 4 2.59 5 2.60 6 2.63

It is seen that the samples are very homogeneous and that the dosagecorresponds to the expected value of 2.60 g for 5 ml.

This formulation can therefore be administered without risk ofoverdosing or underdosing.

Key to Figures

FIG. 1:

dissous=dissolved

profil initial=initial profile

profil aprés 10 jours=profile after 10 days

heures=hours

FIG. 2:

Profil initial=Initial profile

Profil aprés 19 jours=Profile after 19 days

FIG. 3:

dissous Metformine=metformin dissolved

Profil initial=Initial profile

Profil aprés 12 jours=Profile after 12 days

Temps (en heures)=Time (in hours)

1. A suspension of microcapsules in an aqueous liquid phase that allowsmodified release of at least one active principle and is intended fororal administration, wherein said suspension comprises a plurality ofmicrocapsules and an aqueous liquid phase, wherein the aqueous liquidphase is saturated or becomes saturated with active principle(s) oncontact with the microcapsules, and wherein each microcapsule comprises(a) a core comprising at least one active principle(s), wherein none ofthe at least one active principle(s) is amoxicillin and (b) a filmcoating that: (i) is applied to the core, (ii) controls the modifiedrelease of the active principle(s) in gastrointestinal tract fluids, and(iii) comprises: (1) at least one film-forming polymer (P1) insoluble ingastrointestinal tract fluids, present in an amount of 50 to 90% by dryweight based on the total weight of the coating composition, and whereinat least one of said at least one film-forming polymer (P1) is awater-insoluble cellulose derivative; (2) at least onenitrogen-containing polymer (P2) present in an amount of 2 to 25% by dryweight based on the total weight of the coating composition, and whereinat least one of said at least one nitrogen-containing polymer (P2) isselected from the group consisting of: polyacrylamide,poly-N-vinylamide, and poly-N-vinyllactam; (3) at least one plasticizerpresent in an amount of 2 to 20% by dry weight based on the total weightof the coating composition, and wherein at least one of said at leastone plasticizer is selected from the group consisting of: glycerolesters, phthalates, citrates, sebacates, cetyl alcohol esters, andcastor oil; and (4) at least one surfactant or lubricant present in anamount of 2 to 20% by dry weight based on the total weight of thecoating composition, and wherein at least one of said at least onesurfactant or lubricant is selected from the group consisting of:anionic surfactants, non-ionic surfactants, and lubricants, and mixturesthereof; and wherein the in vitro release profile of the suspension ofmicrocapsules in an aqueous liquid phase on day ten is similar to therelease profile on day zero, as measured using a type II apparatusaccording to the European Pharmacopoeia 3rd edition, in a phosphatebuffer medium of pH 6.8, at a temperature of 37° C.
 2. The suspensionaccording to claim 1, wherein at least one of the at least onefilm-forming polymer (P1) is selected from the group consisting of ethylcellulose and cellulose acetate; at least one of the at least onenitrogen-containing polymer (P2) is selected from the group consistingof polyacrylamide and polyvinylpyrrolidone; at least one of the at leastone plasticizer is castor oil; at least one of the at least onesurfactant or lubricant is selected from the group consisting of: analkali metal salt of fatty acids, stearic acid, oleic acid, apolyethoxylated sorbitan ester, a polyethoxylated castor oil derivative,a stearate, a stearylfumarate, sodium stearylfumarate, glycerolbehenate, and mixtures thereof
 3. The suspension according to claim 1,wherein the film coating consists of a single layer.
 4. The suspensionaccording to claim 1, wherein said suspension comprises 30 to 95% byweight of liquid phase; and 5 to 70% by weight of microcapsules.
 5. Thesuspension according to claim 1, wherein the proportion of dissolvedactive principle(s) originating from the microcapsules is less than orequal to 15% by weight of the total weight of the active principle(s)contained in the microcapsules.
 6. The suspension according to claim 1,wherein the active principle(s) contained in the microcapsules saturatesthe liquid phase.
 7. The suspension according to claim 1, wherein theaqueous liquid phase is at least partially saturated with activeprinciple(s) by means of non- encapsulated active principle(s) prior tothe incorporation of the microcapsules into the aqueous liquid phase. 8.The suspension according to claim 1 wherein the microcapsules have aparticle size less than or equal to 1000 microns.
 9. The suspensionaccording to claim 1 wherein from 1 to 50% of the total weight of thecoated microcapsules is film coating.
 10. The suspension according toclaim 9, having an in vitro release profile obtained using a type IIapparatus according to the European Pharmacopoeia 3rd edition, in aphosphate buffer medium of pH 6.8 and at a temperature of 37° C., suchthat: the proportion PI of active principle(s) released during the first15 minutes of the dissolution test is such that: PI≦15; and theremaining active principle(s) is (are) released over a period such thatthe release time of 50% by weight of active principle (t_(1/2)) isdefined as follows (in hours): 0.5≦t_(1/2)≦30.
 11. The suspensionaccording to claim 1 wherein the pH of the suspension is arbitrarilyacidic or neutral.
 12. The suspension according to claim 1 wherein thesuspension comprises at least one rheology modifier.
 13. The suspensionaccording to claim 1 wherein the suspension further comprises at leastone agent for modifying the solubility of the active principle(s) in theaqueous liquid phase.
 14. The suspension according to claim 1 whereinthe suspension further comprises at least one additive selected from thegroup consisting of: surfactants, colourants, dispersants,preservatives, taste improvers, flavourings, sweeteners, antioxidants,and mixtures thereof.
 15. The suspension according to claim 1 wherein atleast one of the at least one active principle(s) is selected from thegroup consisting of: antiulcer drugs, antidiabetics, anticoagulants,antithrombics, hypolipidaemics, antiarrhythmics, vasodilators,antiangina drugs, antihypertensives, vasoprotectors, fertilitypromoters, labour inducers and inhibitors, contraceptives, antibiotics,antifungals, antivirals, anticancer drugs, anti-inflammatories,analgesics, antiepileptics, antiparkinsonism drugs, neuroleptics,hypnotics, anxiolytics, psychostimulants, antimigraine drugs,antidepressants, antitussives, antihistamines, and antiallergics; andwherein none of the at least one active principle(s) is amoxicillin. 16.The suspension according to claim 15, wherein at least one of the atleast one active principle(s) is selected from the group consisting of:pentoxifylline, prazosin, aciclovir, nifedipine, diltiazem, naproxen,ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin,diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride,captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol,salbutamol, carbamazepine, ranitidine, enalapril, simvastatin,fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir,spironolactone, 5-asa, quinidine, perindopril, morphine, pentazocine,metformin, paracetamol, omeprazole, metoclopramide, atenolol, salbutamolmorphine, verapamil, erythromycin, caffeine, furosemide, cephalosporins,montelukast, valaciclovir, ascorbic acid salts, diazepam, theophylline,ciprofloxacin, vancomycin, aminoglycosides, penicillins; and whereinnone of the at least one active principle(s) is amoxicillin.
 17. A drugcomprising a suspension according to claim
 1. 18. A kit for preparingthe suspension according to claim 1, wherein said kit comprises:microcapsules in substantially dry form-comprising the activeprinciple(s) for saturating the liquid phase with active principle(s)once the solid form and liquid phase have been brought into contact; amixture of microcapsules in substantially dry form containing the activeprinciple(s) in the dose that is just necessary for modified release,wherein the microcapsules for modified release comprise a film coatingthat: (i) is applied to a core comprising active principle(s), whereinnone of the active principle(s) is amoxicillin, (ii) controls themodified release of the active principle(s) in gastrointestinal tractfluids, and (iii) comprises: (1) at least one film-forming polymer (P 1)insoluble in gastrointestinal tract fluids, present in an amount of 50to 90% by dry weight based on the total weight of the coatingcomposition, and wherein at least one of said at least one film-formingpolymer (P 1) is a water-insoluble cellulose derivative; (2) at leastone nitrogen-containing polymer (P2) present in an amount of 2 to 25% bydry weight based on the total weight of the coating composition, andwherein at least one of said at least one nitrogen-containing polymer(P2) is selected from the group consisting of: polyacrylamide,poly-N-vinyl amide, and poly-N-vinyl lactam; (3) at least oneplasticizer present in an amount of 2 to 20% by dry weight based on thetotal weight of the coating composition, and wherein at least one ofsaid at least one plasticizer is selected from the group consisting of:glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters,and castor oil; and (4) at least one surfactant or lubricant present inan amount of 2 to 20% by dry weight based on the total weight of thecoating composition, and wherein at least one of said at least onesurfactant or lubricant is selected from the group consisting of:anionic surfactants, non-ionic surfactants, and lubricants, and mixturesthereof; and wherein the in vitro release profile of the suspension ofmicrocapsules in an aqueous liquid phase on day ten is similar to therelease profile on day zero, as measured using a type II apparatusaccording to the European Pharmacopoeia 3rd edition, in a phosphatebuffer medium of pH 6.8, at a temperature of 37° C; together withimmediate-release uncoated active principle(s) in a necessary andsufficient dose to saturate the liquid phase with active principle(s)once the saturation dose of active principle(s) and the liquid phasehave been brought into contact; the liquid phase; at least part of theingredients useful for its preparation; the protocol for preparation ofthe suspension; or combinations thereof
 19. The suspension according toclaim 4, wherein said suspension comprises 60 to 85% by weight of liquidphase.
 20. The suspension according to claim 4, wherein said suspensioncomprises 15 to 40% by weight of microcapsules.
 21. The suspensionaccording to claim 1, wherein the proportion of dissolved activeprinciple(s) originating from the microcapsules is less than or equal to5% by weight of the total weight of the active principle(s) contained inthe microcapsules.
 22. The suspension according to claim 1 wherein themicrocapsules have a particle size of between 200 and 800 microns. 23.The suspension according to claim 1 wherein the microcapsules have aparticle size of between 200 and 600 microns.
 24. The suspensionaccording to claim 1 wherein from 5 to 40% of the total weight of thecoated microcapsules is film coating.
 25. The suspension according toclaim 10, wherein the proportion PI of active principle(s) releasedduring the first 15 minutes of the dissolution test is such that: PI≦5and the remaining active principle(s) is (are) released over a periodsuch that the release time of 50% by weight of active principle(t_(1/12)) is defined as follows (in hours): 0.5≦t_(1/2)≦20.